Principal Investigator/Program Director (Last, first, middle): Shashidharan, Pullani RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A3111-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract abstract.pdf Mime Type: application/octet-stream 7. * Project Narrative projplan.pdf Mime Type: application/octet-stream 8. Bibliography &References Cited ref.pdf Mime Type: application/octet-stream 9. Facilities &Other Resources Facilities_Upload.pdf Mime Type: application/octet-stream 10. Equipment Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Shashidharan, Pullani DYT1 dystonia is a potentially disabling hyperkinetic movement disorder characterized by sustained or repetitive involuntary muscle contractions and/or abnormal postures. The disorder is caused by a three base pair in-frame deletion in the DYT1 gene resulting in the loss of a glutamic acid residue at position 302/303 in torsinA. In our laboratory we have generated two transgenic mouse models that overexpress human mutant torsinA and develop an abnormal phenotype. The first was generated using a rat neuron-specific enolase promoter and the second a mouse DYT1 promoter (see preliminary data). Interestingly, behavioral alterations develop at approximately 3 weeks, and only 40% of transgenic mice exhibit an abnormal phenotype, a pattern similar to what is seen in human DYT1 dystonia. The basis of why some animals exhibit an abnormal phenotype and others do not is not known. We have shown that dopamine levels are reduced and extracellular glutamate levels are increased in the striatum of transgenic mice. Furthermore, yeast two-hybrid screening identified two important torsinA interacting proteins (TAIP), TAIP1 is implicated in the neurotransmission. Based on the studies performed on our current transgenic model and preliminary data obtained, there is enough evidence suggesting an alteration in neurotransmission, which could underlie the pathophysiology of DYT1 dystonia. In this proposal we will 1) Investigate neurochemical and ultra-structural changes in transgenic mouse models;2) Investigate the neuroanatomical changes by unbiased stereology to determine the underylying pathology in the two DYT1 transgenic mouse models;3) Determine the role of TAIP1 in neurotransmission and the effect of torsinA mutation on this function;and 4) Investigate the the effect of crossing TAIP1 knockout mice with DYT1 transgenic mice. The long-term goals are to delineate the pathophysiology and develop novel therapeutic agents and ultimately find a cure for this highly debilitating disorder in children. Project Description Page 6